The present invention, in some embodiments thereof, relates to T cell populations capable of treating cancer. Current therapeutic strategies focus predominantly on achieving the removal or death of cancer cells within the patient, through a diverse array of surgical and non-surgical techniques; the most widely used are chemotherapy and gamma irradiation. Those methods have a number of prominent disadvantages, in particular the culling of healthy cells/tissues within the patient, and the toxic side-effects of the current generation of chemotherapeutic drugs utilized in cancer treatment. Furthermore, these treatments are not always successful.
The spontaneous regression of certain cancers, such as melanoma or renal cell cancer, supports the idea that the immune system is sometimes capable of delaying tumor progression and on rare occasions eliminating a tumor altogether. These observations have led to research interest in a variety of immunologic therapies designed to stimulate the immune system.
Further evidence that an immune response to cancer exists in humans is provided by the existence of lymphocytes within melanoma deposits. These lymphocytes, when isolated, are capable of recognizing specific tumor antigens on autologous and allogeneic melanomas in an MHC restricted fashion. Tumor infiltrating lymphocytes (TILs) from patients with metastatic melanoma recognize shared antigens including melanocyte-melanoma lineage specific tissue antigens in vitro (Kawakami, Y., et al., (1993) J. Immunother. 14: 88-93; Anichini, A. et al., (1993) et al., J. Exp. Med. 177: 989-998). Anti-melanoma T cells appear to be enriched in TILs probably as a consequence of clonal expansion and accumulation at the tumor site in vivo (Sensi, M., et al., (1993) J. Exp. Med. 178:1231-1246).
The term adoptive immunotherapy describes the transfer of immunocompetent cells such as the TILs described herein above to the tumor-bearing host. Adoptive cell transfer (ACT) therapy for patients with cancer relies on the ex vivo generation of highly active tumor, specific lymphocytes, and their administration in large numbers to the autologous host.
Presently, ACT therapy however effectively treats only a limited number of patients. Preclinical models have identified a variety of ways to manipulate the host immune environment that increase ACT therapeutic efficacy. These include immunosuppression prior to cell administration and concurrent interleukin 2 administration with the transferred T cells.
Preclinical models have also identified characteristics of lymphocyte cultures that are required for successful ACT therapy. Until presently, the most important characteristic was thought to be the presence of high affinity, tumor antigen specific CD8+ cells. It was also shown that CD4+ cells were also required for effective treatment of some tumors [Surman et al, J. Immunology 164, 562-565, 2000]. In addition, it has been demonstrated that the presence of CD4+CD25+ T cells suppress autoimmunity and may be potent inhibitors of antitumor effects in mice [Shevach E. M. Nat. Rev. Immunol. 2, 389-400 (2002)]. This has led to the conclusion that lymphodepleting subpopulations comprising this signature may be beneficial for ACT therapy.
Some functional requirements of the cells for effective ACT were elucidated in animal models. For example, the secretion of IFN-γ by injected TILs was shown to significantly correlate with in vivo regression of murine tumors suggesting activation of T-cells by the tumor antigens (Barth, R. J., et al., (1991) J. Exp. Med. 173:647-658). Accordingly, selection of tumor-reactive T cells for adoptive immunotherapy may be effected by analyzing IFN-γ secretion following exposure to tumor antigens. Despite its clinical importance, little is known about the underlying composition and cellular interactions that determine the degree of TIL reactivity as measured by IFN-γ secretion and consequentially on how to control this reactivity.